ES2355586T3 - DROSPIRENONE PREPARATION PROCEDURE. - Google Patents

Abstract

A process for the preparation of Drospirenone (I) according to the following scheme wherein the substituent R is defined in the description. The process improves the product yield and purity by reducing the formation of undesired side-products and is particularly convenient for industrial-scale manufacturing.

Description

 The present invention relates to a new process for the preparation of drospirenone and synthetic intermediates thereof. In comparison with the known drospirenone synthesis routes, the process of the invention allows higher product yields, high purity and can be performed on an industrial scale.

STATE OF THE TECHNIQUE 5

 Drospirenone is a synthetic progestin widely used in contraceptive therapy. Chemically known as 6, 7, 15, 16-dimethylene-3-oxo-17-pregn-4-en-21,17-carbolactone, it has the following structural formula I.

 So far, several synthetic routes have been proposed for the production of drospirenone, for example, in US 6121465, WO 2006/059168, WO 2006/061309, US 2005/0192450, WO 2007/009821, US 6933395 and US 4416985. A synthesis route common to many procedures starts from 7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androsten-17-one 1, which is transformed into 3, 5-dihydroxy -6, 7, 15, 16-dimethylene-5-androst-17-one 6 through the following stages:

 fifteen

 Then, intermediate 6 is converted into the propinol derivative 7 by reaction with propargyl alcohol.

 5

 The triple bond in the carbon chain 17 is hydrogenated and the (3-hydroxypropyl) thus obtained is properly oxidized with simultaneous oxidative lactonization at position 17, dehydration at positions 4-5 and carbonyl formation in carbon 3 , to give drospirenone (I). Different oxidation agents may be used in the final stage, such as chromium oxide (VI) in water / pyridine at 50 ° C (US 4416985), manganese dioxide in toluene at a temperature between 40 ° C and 110 ° C (US 2005/0192450) , ruthenium salts with NaBrO3 in mixture 10 of acetonitrile-water (US 6121465) or alkaline hypochlorite (WO 2007/009821). In all cases, the reduction of the propinol group at position 17 and subsequent oxidative lactonization can affect the performance of the process and cause unwanted epimerization.

DESCRIPTION OF THE INVENTION

 The invention provides a process for the production of drospirenone that improves the yield and purity of the product, reducing the formation of unwanted by-products, such as epimers, and which is particularly suitable for manufacturing on an industrial scale, according to the following steps. :

 1) react the compound of formula 6

 with a compound of formula II: 20

 in which X is halogen and R- is

-CH2-ORI, in which RI is a hydroxyl protecting group that is:

i) a silyl derivative Q3Si-, wherein Q, independently of each other, represents (C1-C6) alkyl, aryl (C6-C10), alkylaryl (C1-C4) or alkoxyaryl (C1-C4), or 5

ii)

in which n is 1 or 2;

whereby a compound of formula 8 is obtained:

 10

 2) oxidation of a compound of formula 8 with removal of the RI, RII or RIII protecting groups to give drospirenone I:

 In a preferred embodiment of the invention, in compound II R is -CH2-ORI, wherein RI is selected from the group consisting of trimethylsilyl-, tert-butyldimethylsilyl-, triethylsilyl-, triisopropylsilyl-, dimethylisopropylsilyl-, diethylisopropylsilyl -, dimethyl (2,3-dimethylbutyl) silyl-, tert-butyldiphenylsilyl-, tribencylsilyl-, tri-p-xylsilyl-, diphenylmethylsilyl-, di-tert-butylmethylsilyl-, dimethylphenylsilyl-, 3,5-bis (trifluoromethyl) phenyldimethylsilyl -, tert-butylmethoxyphenylsilyl-, tert-butoxyphenylsilyl-, (chloromethyl) dimethylsilyl-, allyldimethylsilyl-, triphenylsilyl-.

 In a further preferred embodiment, reaction step 1 is performed in an aprotic solvent in the presence of lithium. Alternatively, compound II is transformed into the corresponding alkyl magnesium derivative before its reaction with compound 6.

 The oxidation according to stage 2 is carried out using an oxidant based on MnIV / VII, in a single stage or in two or three stages, with or without isolation of the intermediate or intermediates, depending on the specific oxidation agent employed and the conditions Reaction taken. Preferably, the oxidant based on MnIV / VII is selected from:

i) MnO2; 5

ii) KMnO4;

 In one embodiment, compound 8 with R = -CH2-ORI in which RI is alkyl (aryl) silyl, is first oxidized in ring "A" with manganese dioxide to produce intermediate 9, which is then hydrolyzed to remove the RI group, thereby producing intermediate 10: 10

which can be isolated and then oxidized in lactone with manganese dioxide, to produce drospirenone.

 In a further embodiment, compound 8 with R = -CH2-ORI in which RI is alkyl (aryl) silyl is hydrolyzed to give intermediate 11:

 fifteen

which can be purified by crystallization and then oxidized with manganese dioxide to produce drospirenone. This alternative oxidation process allows the use of chromium to be completely avoided.

 The following conditions that can be applied to the oxidation stage are particularly preferred:

i) MnO2 in toluene or in one or more of the following solvents: tetrahydrofuran, acetonitrile, dimethylsulfoxide, N, N-dimethylformamide, acetone, at a temperature ranging from 40 ° C to 110 ° C; twenty

ii) KMnO4 in water / acetone in the presence of an aprotic acid at a temperature ranging from -10 ° C to 40 ° C.

 At the end of the procedure, drospirenone can be purified directly by crystallization.

 The starting compound 6 (3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androstan-17-one) can be prepared by

known methods - reference is specifically made to US4416985, Example 1 steps (a) to (f) and US2005 / 0192450, page 6, Example 4. In a preferred embodiment of the invention, compound 6 is prepared according to the following stages:

a) epoxidation of 7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androsten-17-one (1) with tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate in toluene at 70-75 ° C , to give 5,6-epoxy-7-hydroxy-5 15, 16-methylene-3-pivaloyloxy-5-androstan-17-one 2:

b) reacting compound 2 with hexachloroacetone in dichloromethane added together with triphenylphosphine at a temperature of 0-5 ° C followed by heating at 10-15 ° C, to produce 7-chloro-5,6-epoxy-15, 16- methylene-3-pivaloyloxy-5-androstan-17-one 3: 10

c) opening the epoxy ring of compound 3 with simultaneous removal of the chlorine atom, by reaction with acetic acid, zinc and copper bromide with 1,2-dimethoxyethane with heating to 70 ° C, to obtain 5-hydroxy-15, 16 -methylene-3-pivaloyloxy-5-androst-6-en-17-one 4:

 fifteen

d) removal of the pivaloyl group on carbon 3 of compound 4 with potassium hydroxide in a tetrahydrofuran / methanol mixture in the presence of sodium perchlorate at room temperature, followed by the addition of sulfuric acid to pH 7, whereby 3 is obtained , 5-dihydroxy-15, 16b-methylene-5-androst-6-en-17-one 5:

e) conversion of compound 5 into 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one 6 by reaction with dibromomethane in 1,2-dimethoxyethane in the presence of copper and zinc bromide by heating to 75 ° C, followed by the addition of acetic acid and isopropanol:

 5

 The starting compound 7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androsten-17-one 1 is commercially available or can be prepared as described in US4416985 (Example 4).

 A further aspect of the invention relates to the following compounds:

in which R is as defined above, as intermediates for the synthesis of drospirenone. 10

 Unlike the known methods for preparing drospirenone, the process of the invention has the advantage of avoiding any hydrogenation stage, which usually produces not only 17- [3-hydroxypropyl] -6, 7, 15b, 16b-dimethylene -5-androstan-3, 5.17-triol, but also 6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-trihydroxy-21.17 -carbolactol, together with partially hydrogenated by-products. Therefore, the isolation of these desired products - triol and carbolactol - is very problematic and causes the loss of products. fifteen

 In addition, the preparation of compound 8 according to the invention can be carried out without any specific equipment, which is required instead when hydrogenation is needed. Dispense with the hydrogenation stage makes the whole process more attractive on an industrial scale.

 An additional important advantage associated with the invention is the fact that no purification by column chromatography is needed to isolate the intermediates, especially in the case of silyl derivatives that can be oxidized directly to give drospirenone without being isolated. In this case, crude drospirenone has an HPLC purity level of 95-96% and therefore may only need crystallization (for example, in acetone) to meet the requirements of the pharmacopoeia.

 The following examples illustrate the invention in greater detail.

EXAMPLE 1

5,6-Epoxy-7-hydroxy-15-16-methylene-3-pivaloyloxy-5-androstan-17-one

 7-Hydroxy-15, 16-methylene-3-pivaloyloxy-5-androsten-17-one (200.00 g, 0.500 mol) was dissolved in toluene (1610 ml) at 70-75 ° C in an atmosphere of nitrogen in the presence of vanadyl acetylacetonate (1.02 g, 0.004 mol).

 A solution of tert-butyl hydroperoxide (5.5 M in decane, 135 ml, 0.742 mol) in 5 toluene (231 ml) was added dropwise. After two hours, TLC analysis revealed that the reaction was complete and sodium chloride in water (6%, 700 ml) was added. The system was stirred for five minutes and the two phases separated. The organic phase was washed twice with a solution of sodium chloride in water (6%, 2 x 600 ml). The aqueous phase was extracted with toluene (250 ml), the combined organic phases were washed twice with sodium chloride in water (6%, 2 x 50 ml) and concentrated at 50 ° C under reduced pressure, giving a final volume of approximately 300 ml. Then, n-10 hexane (760 ml) was added, the product was filtered and washed with n-hexane. After drying at 45 ° C in a vacuum oven, the title compound was obtained as a colorless powder (187.7 g, 0.451 mol, 90%).

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.93 (s, 3H, CH3-18); 2.14-0.91 (17H); 1.05 (s, 3H, CH3-19); 1.17 (s, 9H, C (CH3) 3); 2.32 (m, 1H, H-17); 3.25 (d, 1H, J = 0.9 Hz, H-6); 3.75 (dd, 1H, J = 8.7, 0.9 Hz, H-7); 4.74 (m, 1 H, H-3).

 13C NMR {300 MHz, CDCl3,  (ppm)}: 16.6 (CH3); 17.3 (CH3); 19.6 (CH3); 20.6 (CH2); 25.2 (CH); 26.5 (CH); 26.9 15 (CH2); 27.0 (3 x CH3, C (CH3) 3); 34.7 (C); 34.9 (CH2); 36.3 (CH); 36.5 (CH2); 37.4 (CH2); 38.5 (C); 42.1 (C); 49.9 (CH); 50.7 (CH); 66.7 (C); 67.2 (CH); 70.2 (CH); 73.3 (CH); 177.9 (C); 216.1 (C)

 HPLC-MS (ESI): [M + H] + = 417; [M + Na] + = 439; [M + K] + = 455; [2 M + Na] + = 855

EXAMPLE 2

7-Chloro-5,6-epoxy-15, 16-methylene-3-pivaloyloxy-5-androstan-17-one 20

 A solution of 5,6-epoxy-7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androstan-17-one (1.66 g, 0.004 mol) in dichloromethane ( 8 ml) with hexachloroacetone (2 ml, 0.013 mol) and cooled to 0-2 ° C. Triphenylphosphine (1.53 g, 0.0044 mol) in dichloromethane (4 ml) was added dropwise and the mixture was stirred for an hour at 3-4 ° C and then for an additional hour at 10-15 ° C. 25

 The reaction mixture was diluted with dichloromethane (20 ml) and washed three times with water. The combined aqueous phases were extracted with dichloromethane and the organic phases were dried over sodium sulfate and concentrated at 45 ° C under reduced pressure. The residue was suspended in ethanol (5 ml), stirred for 15 minutes and filtered. After drying at 40 ° C under vacuum, the title compound was obtained as a colorless solid (1.40 g, 0.003 mol, 80%).

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.94 (s, 3H, CH3-18); 2.17-1.12 (17H); 1.05 (s, 3H, CH3-19); 1.17 (s, 9H, 30 C (CH3) 3); 3.36 (d, J = 3 Hz, 1H, H-6); 4.68 (m, 1H, H-7); 4.79 (m, 1H, H-3).

 13C NMR {300 MHz, CDCl3,  (ppm)}: 16.9 (CH2); 17.4 (CH3); 19.9 (CH); 20.5 (CH2); 20.8 (CH3); 25.6 (CH2); 26.7 (CH); 27.0 (3 x CH3, C (CH3) 3); 31.9 (CH); 35.0 (C); 35.3 (C); 35.9 (CH2); 37.3 (CH2); 38.5 (CH2); 42.0 (CH); 43.5 (C); 48.5 (CH); 55.0 (CH); 64.1 (C); 65.1 (CH); 70.5 (CH); 177.8 (C); 215.1 (C).

 HPLC-MS (ESI): [M + H] + = 435 and 437; [2 M + Na] + = 891 and 893 35

EXAMPLE 3

5-Hydroxy-15, 16-methylene- 3-pivaloyloxy-5-androst-6-en-17-one

 A suspension of zinc powder (2.95 g, 0.045 mol) in 1,2-dimethoxyethane (37 ml) was treated with copper (I) bromide (0.07 g, 0.0005 mol) and heated to 70 ° C . After stirring for 15 minutes, acetic acid 5 (1.11 ml, 0.019 mol) was added followed by 7-chloro-5,6-epoxy-15, 16-methylene-3-pivaloyloxy-5- androstan-17-one (1.30 g, 0.003 mol). The mixture was stirred at 70 ° C for 6 hours and then at room temperature for 16 hours. The reaction was checked by TLC analysis; The mixture was filtered on a bed of celite, washing with tetrahydrofuran (37 ml). The filtrate was treated with triethylamine (1.66 ml) and filtered again. The solid was suspended in a 5% acetic acid solution (37 ml) and then filtered (1.11 g). 10

 The product was crystallized from ethyl acetate / dichloromethane (0.92 g, 0.002 mol, 77%)

 1H NMR {200MHz, CDCl3,  (ppm)}: 0.99 (s, 3H, CH3-18); 1.01 (s, 3H, CH3-19); 1.1-2.4 (17H) 1.24 (s, 9H, C (CH3) 3); 2.84 (s, 1 H, OH-5); 5.16 (s a, 1H, H-3); 5.58 (dd, J = 2.6, 10.2 Hz, 1H, H-7); 5.75 (dd, J = 1.2, 10.2 Hz, 1H, H-6).

 13C NMR {200 MHz, CDCl3,  (ppm)}: 17.6 (CH2); 18.3 (CH3); 20.4 (CH3); 20.5 (CH2); 22.1 (CH); 24.7 (CH2) 15 25.5 (CH2); 26.0 (CH); 27.3 (3 x CH3); 35.3 (CH2); 35.7 (CH); 39.4 (C); 39.5 (CH2); 43.0 (C); 44.8 (CH); 50.8 (CH); 70.3 (CH); 74.3 (C); 126.6 (CH); 135.4 (CH); 177.0 (C); 198.1 (C); 215.9 (C).

 HPLC-MS (ESI): [M + Na] + = 423; [M + K] + = 439

EXAMPLE 4

3, 5-Dihydroxy-15, 16-methylene-5-androst-6-en-17-one 20

 5-Hydroxy-15, 16-methylene-3-pivaloyloxy-5-androst-6-en-17-one (80.00 g, 0.200 mol) was suspended under a nitrogen atmosphere in tetrahydrofuran (800 ml ), was mechanically stirred and cooled to 0-2 ° C. A solution of potassium hydroxide (85%, 27.69 g, 0.419 mol) in methanol (410 ml) was added dropwise below 5 ° C followed by sodium perchlorate monohydrate (7.85 g, 0.056 mol). The mixture was stirred at room temperature for 3-4 hours. After cooling to 4-5 ° C, water (400 ml) was added followed by 20% sulfuric acid in water (90 ml) by adjusting the pH to 7 and the mixture was stirred for 10-15 minutes. Then, tetrahydrofuran and methanol were removed at 40 ° C under reduced pressure and the residue was diluted with water (300 ml). The suspension was stirred at 5 ° C for 30 minutes and the solid was filtered, washed with water and dried at 45 ° C in a vacuum oven for 16 hours. The title compound was obtained as a colorless solid (61.00 g, 0.192 mol, 97%) and was used in the next step without purification. 30

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.995 (s, 3H, CH3-18); 1.02 (s, 3H, CH3-19); 1.1-2.3 (17H); 2.85 (m, 1 H, OH); 3.04 (m, 1 H, OH); 4.13 (m, 1H, H-3); 5.58 (dd, J = 2.8, 10 Hz, 1H, H-7); 5.73 (dd, J = 1.6, 10 Hz, 1H, H-6).

 13C NMR {200 MHz, CDCl3,  (ppm)}: 17.5 (CH2); 18.0 (CH3); 20.2 (CH3); 20.3 (CH2); 22.0 (CH); 24.5 (CH2); 25.7 (CH); 27.7 (CH2); 35.1 (CH2); 35.5 (CH); 39.1 (C) 40.6 (CH2); 42.8 (C); 44.6 (CH); 50.5 (CH); 66.9 (CH); 75.5 (C); 126.0 (CH); 135.4 (CH); 216.2 (C). 35

 HPLC-MS (ESI): [M + H] + = 317; [M + Na] + = 439; [M + K] + = 355 [2 M + Na] + = 655

EXAMPLE 5

3, 5-Dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one

 Zinc (powder, 135.00 g, 2.065 mol) and copper (I) bromide (5.00 g, 0.035 mol) were suspended in 1,2-dimethoxyethane (1820 ml) under a nitrogen atmosphere; The mixture was heated to 75 ° C and stirred for 20 minutes. 5 3, 5-Dihydroxy-15, 16-methylene-5-androst-6-en-17-one (100.00 g, 0.316 mol) was added and the mixture was stirred for 15 minutes. Then, the system was treated with acetic acid (4.5 ml, 0.078 mol) and isopropanol (9.5 ml, 0.124 mol) and stirred at 72 ° C. A solution of dibromomethane (334 g, 1,921 mol) in 1,2-dimethoxyethane (114 ml) was added dropwise at such a rate that the temperature was maintained at approximately 75 ° C. The mixture was stirred for one hour until TLC analysis revealed that the conversion of the starting material was complete. 10

 Ethyl acetate (2500 ml) was added and the system was cooled to 0-5 ° C. After slowly adding 5% acetic acid in water (2500 L), stirring was maintained for 30 minutes. The solid was filtered and the liquid phases were separated. The aqueous phase was extracted twice with ethyl acetate (1250 ml, 500 ml) and the combined organic phases were washed twice with water (2 x 2500 ml) and separated. After removing the organic solvent at 45 ° C under reduced pressure, the residue was taken up in diisopropyl ether (560 ml), stirred, filtered and washed twice with diisopropyl ether. The title compound was dried at 45 ° C under vacuum (74.50 g, 0.225 mol, 71%).

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.86 (s, 3H, CH3-18); 0.6-2.3 (21 H); 0.95 (s, 3H, CH3-19); 3.00 (s a, 2H, 2 (OH)); 4.06 (m, 1H, H-3).

 13 C NMR {200MHz, CDCl3,  (ppm)}: 11.7 (CH2); 13.9 (CH); 17.6 (CH2); 19.0 (CH3); 20.1 (CH3); 21.1 (CH2); 22.3 (CH); 25.0 (CH); 25.9 (CH); 26.7 (CH2); 27.6 (CH2); 33.3 (CH); 34.9 (CH2); 40.5 (C); 43.0 (C); 42.9 (CH2); 45.4 (CH); 51.9 20 (CH); 66.9 (CH); 74.5 (C); 216.3 (C).

 HPLC-MS (ESI): [M + Na] + = 353; [2 M + Na] + = 683

EXAMPLE 6

(3-Chloropropoxy) trimethylsilane

 25

 3-Chloropropanol (100.00 g, 1.056 mol) in dichloromethane (1200 ml) was stirred mechanically under a nitrogen atmosphere; After cooling the solution to 0 ° C, triethylamine (176 ml, 1,263 mol) was added.

 Then, a solution of chlorotrimethylsilane (126.40 g, 1,164 mol) in dichloromethane (300 L) was added dropwise maintaining the temperature between 0 ° C and 5 ° C. When the conversion was completed, diisopropyl ether (600 ml) was added and triethylamine hydrochloride was filtered by washing the bed with diisopropyl ether. The filtrate was concentrated at 38 ° C under reduced pressure and the product was purified by distillation (0-5 mmHg, 70 ° C). (3-Chloropropoxy) trimethylsilane was obtained as a colorless liquid (144.57 g, 0.867 mol, 82%).

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.13 (s, 9H, CH3); 1.96 (m, 2H, CH2); 3.65 (t, J = 6.3 Hz, 2H, Cl-CH2); 3.72 (t, J = 5.7 Hz, 2H, O-CH2).

EXAMPLE 7 35

17- [3- (Trimethylsilanyloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol

 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one (65.00 g, 0.197 mol) was dissolved in tetrahydrofuran (975 ml) and cooled to -20 ° C in a nitrogen atmosphere. Then, lithium (granular, 13.5 g, 1.67 mol) was added and stirred for 20 to 30 minutes. (3-Chloropropoxy) trimethylsilane (131.17 g, 0.787 mol) was added dropwise maintaining the temperature below -15 ° C and stirring continued at a temperature between -20 and -15 ° C. The reaction was monitored by TLC analysis and when there was no more starting material (2.5 hours), the mixture was poured into water / ice / sodium bicarbonate (910 ml / 1170 g / 150 g) and stirred vigorously until that the remaining lithium dissolved completely. The mixture was extracted twice with ethyl acetate (1300 ml, 650 ml) and the organic phases were washed with water (325 ml, 160 ml). Removal of the ethyl acetate under reduced pressure provided the crude product (127.1 g, quantitative yield) that was used in the subsequent step without further purification. 10

 A sample of the crude product was further purified, first by decantation, and then by crushing and filtering dichloromethane / n-hexane.

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.21-2.80 (25H); 0.84 (s, 3H, CH3-18); 088 (s, 3H, CH3-19); 3.57-3.75 (m, 6H, 3xOH, CH2-OSi).

 13C NMR {300 MHz, DMSO-d6,  (ppm)}: -0.65 (3 x CH3); 7.7 (CH2); 14.9 (CH); 15.9 (CH); 19.0 (CH3); 19.1 15 (CH3); 21.7 (CH2); 22.7 (CH); 25.4 (CH2); 27.0 (CH2); 27.5 (CH2); 33.5 (CH2); 34.1 (CH); 36.5 (CH2); 40.3 (C); 42.6 (CH2); 43.0 (C); 44.9 (CH); 52.8 (CH); 63.3 (CH2); 66.8 (CH); 67.7 (CH2); 74.5 (C); 81.7 (C).

 HPLC-MS (ESI): [M + Na] + = 485; [2 M + Na] + = 947

EXAMPLE 8

tert-Butyl- (3-chloropropoxy) dimethylsilane 20

 A solution of 3-chloropropanol (84.6 g, 0.895 mol) in dichloromethane (1600 ml) was treated with imidazole (121.9 g, 1,791 mol) under a nitrogen atmosphere and cooled to 0-5 ° C.

 Tert-butylchlorodimethylsilane (100.00 g, 0.663 mol) diluted with dichloromethane (160 ml) was added dropwise at 0-5 ° C. 25

 After 2.5 hours, the reaction was stopped by pouring the mixture into ice / water (423 g / 1270 ml) and stirring for five minutes. The mixture was then allowed to reach 20 ° C and the two phases were separated.

 The aqueous phase was extracted with dichloromethane (850 ml) and the combined organic phases were washed with water (600 ml). The organic phase was concentrated at 40 ° C under reduced pressure, providing the product as a pale yellow oil (159.33 g, 0.763 mol, 85%) which was subsequently used without further purification. 30

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.05 (s, 6H, Si- (CH3) 2); 0.87 (s, 9H, Si-C (CH3) 3); 2.01 (m, 2H, CH2); 3.75 (t, J = 6.3 Hz, 2H, Cl-CH2); 3.82 (t, J = 5.7 Hz, 2H, O-CH2),

EXAMPLE 9

17- [3- [tert-Butyldimethylsilanyloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan- (3, 17-triol

 The compound was prepared as described in EXAMPLE 7 starting from 25.00 g (0.075 mol) of 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17 -one which was treated with lithium (6.03 g, 0.865 mol) and tert-butyl- (3-chloro-propoxy) dimethylsilane (90.74 g, 0.434 mol).

 An oily product (60.10 g, quantitative yield) was obtained and used in the subsequent step without further purification.

 A sample of the compound was purified by column chromatography on silica gel, eluting with n-hexane / ethyl acetate and isolated for analytical characterization.

 1H NMR {300 MHz, DMSO-d6,  (ppm)}: 0.1-2.1 (25H); 0.03 (s, 6H, Si- (CH3) 2); 0.76 (s, 6H, CH3-18 and CH3-19); 0.87 (s, 9H, C (CH3) 3); 3.6 (m, 3H, OH and CH2-22); 3.84 (m, 1H, H-3); 4.35 (s a, 1 H, OH); 4.84 (d, J = 4.2 Hz, 1 H, OH-3). 10

 13C NMR {200 MHz, CDCl3,  (ppm)}: -5.2 (CH3); -5.3 (CH3); 7.9 (CH2); 11.3 (CH); 14.5 (CH); 15.7 (CH); 18.0 (C); 18.9 (CH3); 19.3 (CH); 19.4 (CH3); 22.0 (CH2); 22.6 (CH); 25.2 (CH2); 25.8 (3 x CH3); 27.3 (CH2); 27.8 (CH2); 33.2 (CH2); 34.2 (CH); 36.6 (CH2); 40.0 (C); 42.4 (C); 43.6 (CH2); 52.9 (CH); 63.7 (CH2); 65.9 (CH); 67.0 (CH2); 72.7 (C); 80.6 (C).

 HPLC-MS (ESI): [M + Na] + = 527; [2 M + Na] + = 1031 15

EXAMPLE 10

2- (3-Chloropropoxy) tetrahydropyran

 To a solution of 3-chloropropanol (20.00 g, 0.212 mol) in dichloromethane (100 ml) was added dropwise 3,4-dihydro-2H-pyran (16.02 g, 0.190 mol) diluted in dichloromethane ( 17 ml) at 0-5 ° C. The mixture was stirred for 30 minutes and the reaction was stopped (checked by TLC analysis) by washing with saturated sodium bicarbonate (100 ml). After separation, the organic phase was washed with water (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure at 30 ° C (34.32 g).

 The title compound was isolated by column chromatography on silica gel eluting with n-hexane: ethyl acetate) (31.28 g, 0.175 mol, 91%). 25

 1H NMR {300 MHz, CDCl3,  (ppm)}: 1.2-2.0 (6H); 2.09 (m, 2H, CH2); 3.56 (m, 2H, CI-CH2); 3.70 (m, 2H, O-CH2); 3.92 (m, 2H, O-CH2); 4.65 (m, 1 H, O-CH-O).

 GC-MS (El): [M-H] + = 177; [M-CICH2CH2CH2O] + = 85

EXAMPLE 11

17- [3- (Tetrahydropyran-2-yloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol 30

 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one (8.00 g, 0.024 mol) was dissolved in tetrahydrofuran

(117 ml) and cooled to -20 ° C under a nitrogen atmosphere. Then, lithium (granular, 1.68 g, 0.242 mol) was added and stirred for 20 minutes. 2- (3-Chloropropoxy) tetrahydropyran (21.62 g, 0.121 mol) was added dropwise, keeping the temperature below -15 ° C and stirring was continued at a temperature between -20 and -15 ° C. The reaction was monitored by TLC analysis and when there was no more starting material (2.5 hours), the mixture was poured into water / ice / sodium bicarbonate (112 ml / 16 g / 144 g) and stirred vigorously until the remaining lithium dissolved completely. The mixture was extracted twice with ethyl acetate (160 ml, 80 ml) and the organic phases were washed with water (2 x 40 ml). After separation, removal of the ethyl acetate at 50 ° C under reduced pressure provided 22.50 g of the crude product which was purified by column chromatography on silica gel eluting with n-hexane / ethyl acetate and obtained in form of a colorless powder (11.41 g, 99%).

 1H NMR {300 MHz, DMSO-d6,  (ppm)}: 0.17 (m, 1H, cyclopropyl); 0.47 (m, 1 H, cyclopropyl); 0.64-2.11 (29 H); 10 0.78 (s, 6H, CH3-18 and CH3-19); 3.26-3.85 (m, 5H); 4.16 (s, 1 H, OH); 4.35 (s a, 1 H, OH); 4.55 (m, 1H, O-CH-O); 4.84 (d, 1H, OH-3).

 13C NMR {300 MHz, CDCl3,  (ppm)}: 7.7 (CH2); 11.6 (CH2); 15.0 (CH); 16.0 (CH); 19.0 (CH3); 19.1 (CH3); 19.5 (CH2); 21.7 (CH2); 22.7 (CH); 24.1 (CH2); 25.0 (CH); 25.3 (CH2); 26.7 (CH2); 27.5 (CH2); 30.5 (CH2); 33.7 (CH2); 34.2 (CH); 36.5 (CH2); 40.3 (C); 42.6 (C); 43.0 (CH2); 44.9 (CH); 52.9 (CH); 62.3 (CH2); 66.9 (CH); 68.2 (CH2); 74.6 (C); 15 81.9 (C); 98.7 (CH).

 HPLC-MS (ESI): [M + Na] + = 497.

EXAMPLE 12 (comparative)

17- (2- [1,3] Dioxolan-2-ylethyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol

 twenty

 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one (60.00 g, 0.182 mol) was dissolved in tetrahydrofuran (900 ml) and cooled to -20 ° C. Then, lithium (granular, 13.86 g, 2.003 mol) was added and stirred for 20 to 30 minutes. 2- (2-Bromoethyl) -1,3-dioxolane (180.81 g, 0.999 mol) was added dropwise maintaining the temperature below 0 ° C and stirring was continued between -20 and -15 ° C. The reaction was monitored by TLC analysis and when there was no more starting material (2 hours), the mixture was poured into water / ice / sodium bicarbonate (830 ml / 1070 g / 120 g) and stirred vigorously until the Remaining lithium dissolved completely. The mixture was extracted twice with ethyl acetate (1100 ml, 850 ml) and the organic phases were washed with water (800 ml, 700 ml). After phase separation, removal of ethyl acetate at 50 ° C under reduced pressure provided the crude product as an oily mixture (110.44 g).

 Purification performed by column chromatography on silica gel eluting with n-hexane / ethyl acetate gave the title compound (64.25 g, 0.149 mol, 82%).

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.34-2.28 (26H); 0.86 (s, 3H, CH3-18); 0.90 (s, 3H, CH3-19); 2.54 (s, 1 H, OH-17); 3.34 (d, J = 6Hz, 1H, OH-3); 4.05-3.85 (m, 5 H, H-3, 2 x CH2-O); 4.95 (t, J = 4.6 HZ, 1H, O-CH-O).

 13C NMR {200 MHz, CDCl3,  (ppm)}: 7.8 (CH2); 11.6 (CH2); 15.0 (CH); 16.0 (CH); 19.0 (CH3); 19.2 (CH3); 21.7 (CH2); 22.5 (CH); 25.0 (CH); 26.7 (CH2); 27.6 (CH2); 28.2 (CH2); 30.8 (CH2); 34.2 (CH); 36.5 (CH2); 40.3 (C); 42.7 (C); 35 43.0 (CH2); 44.8 (CH); 52.7 (CH); 64.8 (2 x CH2); 67.0 (CH); 74.7 (C); 81.8 (C); 105.0 (CH).

 HPLC-MS (ESI): [M + Na] + = 455; [M + K] + = 471; [2 M + Na] + = 887

EXAMPLE 13 (comparative)

17- (2- [1,3] Dioxan-2-ylethyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol

 The title compound was prepared as described in EXAMPLE 12 by reaction of 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one (30.00 g, 0.091 mol) with 2- (2-bromoethyl) -1,3-dioxane (97.20 g, 0.498 mol) in the presence of lithium (granular, 7.11 g, 1.024 mol).

 The crude product (66.25 g) was purified by crystallization from dichloromethane (29.5 g, 0.067 mol, 74%). 5

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.24-2.32 (27 H); 0.85 (s, 3H, CH3-18); 0.89 (s, 3H, CH3-19); 2.56 (s, 1H, OH-17); 3.38 (d, J = 6.6 Hz, 1H, OH-3); 3.72-4.15 (m, 6H, H-3, OH, 2 x CH2-O); 4.61 (t, J = 4.9 Hz, 1H, O-CH-O).

 13C NMR {300 MHz, CDCl3,  (ppm)}: 7.8 (CH2); 11.7 (CH2); 15.3 (CH); 16.1 (CH); 19.1 (CH3); 19.3 (CH3); 21.8 (CH); 22.7 (CH2); 25.3 (CH); 25.7 (CH2); 27.7 (CH2); 29.7 (CH2); 31.0 (CH2); 34.2 (CH); 36.6 (CH2); 40.4 (CH2); 42.7 (C); 43.1 (CH2); 44.9 (C); 52.8 (CH); 53.2 (CH); 66.9 (CH2); 67.0 (CH2); 67.1 (CH); 74.9 (C); 81.9 (C); 102.8 (CH). 10

 HPLC-MS (ESI): [M + Na] + = 469; [2 M + Na] + = 915

EXAMPLE 14 (comparative)

17- (3,3-Dimethoxypropyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol

 The title compound was prepared according to EXAMPLE 12 by reaction of 3, 5-dihydroxy-15 6, 7, 15, 16-dimethylene-5-androst-17-one (8.21 g , 0.025 mol) with 3-bromo-1,1-dimethoxypropane (31.25 g, 0.171 mol) in the presence of lithium (granular, 2.42 g, 0.348 mol).

 The crude product (13.80 g) was purified by column chromatography on silica gel eluting with n-hexane / ethyl acetate to give the title compound (9.17 g, 0.021 mol, 84%).

 1H NMR {300 MHz, DMSO-d6,  (ppm)}: 0.13-2.15 (25H); 0.75 (s, 6 H, CH3-18 and CH3-19); 3.21 (s, 6H, 2 x 20 OCH3); 3.83 (m, 1H, CH-3); 4.17 (s, 1 H, OH); 4.31 (m, 2H, OH and CH- (OMe) 2); 4.82 (m, 1H, OH-3).

 13 C NMR {300 MHz, DMSO,  (ppm)}: 7.9 (CH2); 11.5 (CH2); 14.5 (CH); 15.8 (CH); 18.9 (CH3); 19.3 (CH3); 21.9 (CH2); 22.1 (CH); 26.5 (CH2); 26.9 (CH2); 28.1 (CH2); 31.6 (CH2); 34.1 (CH); 38.7 (CH2); 40.0 (C); 42.3 (C); 44.0 (CH2); 45.1 (CH); 51.0 (CH3); 52.2 (CH3); 52.7 (CH); 66.0 (CH); 72.9 (C); 80.5 (C); 105.0 (2 x CH).

 HPLC-MS (ESI): [M + Na] + = 457; [2 M + Na] + = 891 25

EXAMPLE 15 (comparative)

17- (2- [1,3] dioxan-2-ylethyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol

 Magnesium filings (2.35 g, 0.097 mol) were suspended in tetrahydrofuran (8.0 ml) in an atmosphere of

nitrogen in the presence of a small amount of iodine. 2- (2-Bromoethyl) - [1,3] dioxane (18.88 g, 0.097 mol) diluted in tetrahydrofuran (8.0 ml) was added dropwise at a rate such that the temperature was maintained between 55 ° C and 60 ° C . After one hour, the mixture was diluted with tetrahydrofuran (18.0 ml) due to the increase in density. Stirring was continued for another hour.

 A portion (39.39 g) of the prepared solution containing 2- (2-bromomagnesioethyl) -5 [1,3] dioxane (16.80 g, 0.077 mol) was added dropwise at 3, 5-dihydroxy -6, 7, 15, 16-dimethylene-5-androst-17-one (3.00 g, 0.009 mol) previously dissolved in tetrahydrofuran (39.0 ml) under a nitrogen atmosphere. The mixture was stirred for 3.5 hours controlling the reaction by TLC analysis. Then, ice (77.0 g) was added and stirring was continued for 30 minutes. Tetrahydrofuran was removed at 50 ° C under reduced pressure and ethyl acetate (60.0 ml) was added followed by celite (15.0 g). The suspension was stirred for 15 minutes at 25 ° C. After filtering the celite and vigorously washing with ethyl acetate (50 ml), the two phases were separated and the aqueous one was extracted with ethyl acetate (30 ml). The combined organic phases were washed with water (30 ml) and concentrated at 50 ° C under reduced pressure.

 The residue was taken up with tetrahydrofuran and concentrated to dryness, providing the crude product as a slightly yellow oil (5.35 g).

 The title compound was isolated by column chromatography on silica gel eluting with dichloromethane / methanol and was obtained as a colorless solid (3.86 g, 0.0086 mol, 95%).

 The analytical results correspond to those indicated in EXAMPLE 13.

EXAMPLE 16 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 twenty

 A solution of 17- [3- (trimethylsilyloxy) -propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol crude (0.139) was cooled mol) in acetone (1990 ml) and water (81 ml) at -5-0 ° C. Jones reagent (431 g containing: 81 g of chromium oxide (VI), 221 g of water, 127 g of sulfuric acid) was added dropwise at -5 / 0 ° C and the mixture was stirred until analysis by TLC revealed that product training was complete.

 The reaction was stopped by the addition of ice (933 g), sodium pyrosulfite (503 g) and ethyl acetate (933 25 ml) and stirred for 30 minutes allowing the mixture to reach room temperature. After the addition of solid chloride (477 g), the two phases were separated and the aqueous one was extracted with ethyl acetate (834 ml, 417 ml). The combined organic phases were washed with 10% sodium chloride in water (747 ml, 373 ml), saturated sodium bicarbonate (815 ml, 460 ml), 1 M sodium hydroxide (255 ml), saturated sodium bicarbonate (255 ml) and water (255 ml). The organic solvent was removed at 50 ° C under reduced pressure to provide a whitish foam (40.70 g). 30

 The crude product was purified by crystallization from acetone (20.31 g, 0.055 mol, 41%).

 Mp: 200 ° C

 [] 25D (c = 0.5%, CHCl3) = -183º

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.8-2.19 (18H); 0.4-0.6 (m, 1 H, cyclopropyl); 1.00 (s, 3H, CH3-18); 1.09 (s, 3H, CH3-19); 2.39-2.61 (m, 4H, 2 x CH2-C = O); 6.05 (s, 1H, H-4). 35

 13C NMR {200 MHz, CDCl3,  (ppm)}: 9.7 (CH2); 16.5 (CH); 17.4 (CH2); 18.7 (CH3); 18.8 (CH); 19.5 (CH); 19.6 (CH2); 20.7 (CH3); 24.2 (CH); 29.1 (CH2); 30.5 (CH2); 33.8 (CH2); 34.0 (CH); 36.9 (CH2); 37.2 (CH2); 41.5 (C); 51.5 (CH); 51.6 (CH); 95.9 (C); 103.8 (C); 125.6 (CH); 171.1 (C); 176.4 (C); 197.6 (C).

 HPLC-MS (ESI): [M + H] + = 367; [2 M + Na] + = 755

EXAMPLE 17 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 The preparation of the title compound is analogous to that indicated in EXAMPLE 16, starting from 17- [3- (tetrahydropyran-2-yloxy) propyl] -6, 7, 15, 16-dimethylene-5 -androstan-3, 5.17-triol (5.01 g, 0.011 mol).

 The crude product (3.10 g) was crystallized from acetone (2.01 g, 0.005 mol, 51%). 5

 The analytical data correspond to those indicated in EXAMPLE 16.

EXAMPLE 18 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 The preparation is analogous to that indicated in EXAMPLE 16 starting from 17- (2- [1,3] dioxan-2-ylethyl) -10 6, 7, 15, 16-dimethylen-5-androstan -3, 5.17-triol (58.11 g, 0.133 mol).

 The crude product (42.79 g) was filtered through silica gel washing with dichloromethane / methanol. After removing the solvents, crystallization of the solid from acetone gave pure drospirenone (15.03 g, 0.041 mol, 32%).

 The analytical data correspond to those indicated in EXAMPLE 16. 15

EXAMPLE 19 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 17- [3- (trimethylsilyloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol crude (0.111 mol) was dissolved in dimethylsulfoxide (1012 ml) and IBX (88.66 g, 0.317 mol; added according to the procedure indicated in J. Org. Chem., 64 (1999), 4537-4538) was added portionwise at 20 ° C. The mixture was stirred vigorously for 20 hours, monitoring the conversion by TLC analysis. After diluting with ethyl acetate (1000 ml), water (1012 ml) was slowly added and the thick mixture was stirred for 15 minutes. The solid was filtered and washed with ethyl acetate. After adding sodium chloride (100 g) to the filtrate, the collected phases were separated. The aqueous phase was extracted twice with ethyl acetate (900 ml, 600 ml) and the combined organic phases were washed with brine (550 ml), 0.1 N sodium hydroxide (800 ml) and water (700 ml). The organic solution was concentrated at 50 ° C under reduced pressure, the residue was taken up in tetrahydrofuran and concentrated again. The solid was suspended in diisopropyl ether (250 ml) and stirred at 0-5 ° C for 1 hour. Filtration provided a solid that was dried at 45 ° C in a vacuum oven to a

constant weight (40.00 g).

 A solution of the solid in acetone (1200 ml) and water (48 ml) was cooled to 0-5 ° C. Jones reagent (141.80 g containing: 26.8 g of chromium oxide (VI), 73 g of water, 42 g of sulfuric acid) was added dropwise at 0-5 ° C and the mixture was stirred until TLC analysis revealed that product formation was complete.

 The reaction was stopped by the addition of ice (400 g), ethyl acetate (574 ml) and sodium pyrosulfite 5 (167g) and stirring was continued for 30 minutes. After the addition of sodium chloride (45 g), the two phases were separated and the aqueous one was extracted with ethyl acetate (500 ml). The combined organic phases were washed once with 10% sodium chloride in water (500 ml), 1 N sodium hydroxide (400 ml), saturated sodium bicarbonate (400 ml) brine (500 ml) and water (300 ml).

 The ethyl acetate was removed under reduced pressure and the residue was dissolved in dichloromethane (110 ml) and washed with brine (300 ml). After drying over sodium sulfate, the organic solvent was removed at 50 ° C under reduced pressure to provide a whitish foam (33.26 g). Trituration with diisopropyl ether (750 ml) gave 31.00 g of the product.

 After crystallization in acetone, drospirenone (20.92 g, 0.057 mol, 51%) was obtained.

 The analytical data correspond to those indicated in EXAMPLE 16. 15

EXAMPLE 20 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn- 4-en-21.17-carbolactone (Drospirenone)

 (17- [3- (tert-Butyldimethylsilanyloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol (0.39 g) , 0.001 mol) in N, N-dimethylformamide (7 ml) and treated with pyridinium dichromate (2.30 g, 0.006 mol) The reaction was stirred 20 for two hours at 20 ° C and subsequently heated to 50 ° C for three hours .

 Then, a saturated solution of sodium sulphite (15 ml) was added and the mixture was extracted with ethyl acetate (15 ml). When the color turned completely green, the organic phase was separated, washed twice with water (2 x 10 ml) and dried over sodium sulfate. Removal of the solvent under reduced pressure gave the crude product (0.30 g) which was purified on silica gel to give the title compound (0.24 g, 0.0006 mol, 65%). 25

 The analytical data correspond to those indicated in EXAMPLE 16.

EXAMPLE 21

17- [3- (tert-Butyl-dimethylsilanyloxy) propyl] -6, 7, 15, 16-dimethylenandrost-4-en-17-ol-3-one

 17- [3- (tert-Butyldimethylsilanyloxy) propyl] -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol (0.058-30 mol) was dissolved in toluene (924 ml) at 80 ° C and manganese dioxide (IV) (90%, 223.50 g, 2,314 mol) was added portionwise. After 6 hours, more amount of oxidant (20.30 g, 0.210 mol) was added. When the reaction was completed as indicated by TLC analysis, ethyl acetate (460 ml) and water (1850 ml) were added. Then, oxalic acid (417.00 g) was added portionwise for 50 minutes, keeping the temperature below 10 ° C. The mixture was vigorously stirred and the development of carbon dioxide was observed. After allowing the system to reach 35-20 ° C, the two phases separated. The aqueous phase was extracted twice with ethyl acetate (460 ml, 230 ml) and the combined organic phases were washed with water (460 ml, 230 ml) and saturated sodium bicarbonate (460 ml, 230 ml).

 After removing the solvent from the organic phase at 60 ° C under reduced pressure, the crude product was obtained. (29.00 g, quantitative yield).

 A sample was purified by column chromatography, eluting with n-hexane / ethyl acetate, and analyzed.

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.84-1.95 (20H); 0.08 (s, 6H, 3 Si (CH3) 2); 0.31 (m, 1H, cyclopropyl (CH2)); 0.91 (s, 9H, C (CH3)); 0.93 (s, 3H, CH3-18); 1.10 (s, 3H, CH3-19); 2.26-2.68 (m, 3H, CH2-C = O, OH); 3.70 (m, 2H, -CH2O); 5 6.02 (s, 1H, H-4);

 13C NMR {200 MHz, CDCl3,  (ppm)}: -5.4 (2 x CH3); 1.1 (CH2); 15.8 (CH); 17.4 (CH3); 18.2 (C); 18.9 (CH2); 19.0 (CH); 19.1 (CH3); 20.1 (CH); 21.1 (CH2); 23.0 (CH); 25.9 (3 x CH3); 27.0 (CH2); 33.7 (CH2); 33.9 (CH2); 34.7 (CH); 36.4 (CH2); 36.9 (CH2); 37.4 (C); 42.4 (C); 52.0 (CH); 52.5 (CH); 63.8 (CH2); 81.6 (C); 125.5 (CH); 172.1 (C); 198 (C).

 HPLC-MS (ESI): [M + H] + = 485; [M + Na] + = 507; [2 M + Na] + = 991 10

EXAMPLE 22

17- [3-Hydroxypropyl] -6, 7, 15, 16, -dimethylenandrost-4-en-17-ol- 3-one

 A solution of 17- [3-tert-butyldimethylsilanyloxypropyl] -6, 7, 15, 16b-dimethylene-androst-4-en-17-ol-3-one (29.00 g, 0.058) was treated mol) in tetrahydrofuran (435 ml) at 20 ° C with tetra-n-butylammonium fluoride trihydrate (9.18 g, 0.029 mol). Two more portions of fluoride were added after 50 minutes (0.92 g, 0.003 mol) and after 80 minutes (1.84 g, 0.006 mol), respectively.

 After stirring for three hours, no more material separated by TLC was visible and the reaction was stopped by pouring the mixture into a 24% aqueous solution of sodium chloride (650 ml). Stirring was continued for 15 minutes and the phases were subsequently separated. twenty

 The aqueous phase was extracted with ethyl acetate (250 ml), the combined organic phases were washed twice with brine (2 x 250 ml) and concentrated under reduced pressure at 50 ° C. The dark brown oil obtained in this way was taken up in tetrahydrofuran (100 ml) and concentrated again.

 The residue (24.61 g) was suspended in diisopropyl ether / n-hexane (22 ml / 224 ml), the mixture was stirred for 30 minutes at 0 ° C and filtered. The solid was washed with n-hexane (25 ml). The sequence was repeated twice with stirring at 20 ° C. 25

 The solid was dried at 50 ° C in a vacuum oven at a constant weight (15.50 g).

 Further purification by column chromatography, eluting with ethyl acetate / methanol, provided the title compound (7.94 g, 0.021 mol, 37%).

 1H NMR {300 MHz, CDCl3,  (ppm)}: 0.32-2.62 (25H); 0.92 (s, 3H, CH3-18); 1.09 (s, 3H, CH3-19); 3.72 (m, 2H, CH2-O); 6.01 (s, 1H, H-4). 30

 13C NMR {300 MHz, CDCl3,  (ppm)}: 7.8 (CH2); 16.0 (CH); 17.5 (CH3); 18.9 (CH2); 19.0 (CH); 19.2 (CH3); 20.1 (CH); 21.1 (CH2); 22.7 (CH); 27.0 (CH2); 33.8 (CH2); 33.9 (CH2); 34.7 (C); 36.3 (CH); 37.0 (CH2); 37.4 (CH2); 42.5 (C); 52.0 (CH); 52.5 (CH); 63.3 (CH2); 82.0 (C); 125.5 (CH); 172.2 (C); 198.1 (C).

 HPLC-MS (ESI): [M + H] + = 371; [M + K] + = 409; [2 M + Na] + = 763

EXAMPLE 23 35

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 17- [3-Hydroxypropyl] -6, 7, 15, 16-dimethylene-androst-4-en-17-ol-3-one (0.50 g, 0.001 mol) was dissolved in tetrahydrofuran (10 ml) at 55 ° C and manganese dioxide (IV) (90%, 2.50 g, 0.026 mol) was added portionwise. After 6 hours, an additional amount of oxidant (90%, 1.25 g, 0.013 mol) was added. When the reaction was completed as indicated by TLC analysis, tetrahydrofuran (100 ml) was added and the mixture was filtered. The filtrate was concentrated 5 to 50 ° C under reduced pressure to provide the crude product (0.34 g). The title compound was isolated by column chromatography, eluting with n-hexane / ethyl acetate. (0.20 g, 0.0005 mol, 50%).

 The analytical data are in accordance with those indicated in EXAMPLE 16.

EXAMPLE 24

17- [3-Hydroxypropyl] -6, 7, 15 (3,16-dimethylenandrostan-3, 5,17-triol 10

 17- [3- (tert-Butyldimethylsilyloxy) propyl] -6, 7, 15b, 16b-dimethylene-5-androstan-3, 5.17-triol (0.059 mol) dissolved in tetrahydrofuran ( 200 ml) at 0-5 ° C with a solution of tetra-n-butylammonium trihydrate fluoride (9.18 g, 0.029 mol) in tetrahydrofuran (100 ml). After 20 minutes no more starting material was visible by TLC analysis and the reaction was stopped by pouring the mixture into water / ice (200 g / 145 g). Sodium chloride (20 g) was added and the mixture was extracted with ethyl acetate (190 ml). Subsequently, the phases were separated; The organic phase was washed with brine (200 ml, 100 ml) and concentrated at 50 ° C under reduced pressure. The dark brown oil obtained was taken up in tetrahydrofuran (100 ml) and concentrated again.

 The residue was crystallized (29.39 g) in acetone to give the title compound (15.07 g, 0.040 mol, 67%).

 1H NMR {200 MHz, DMSO-d6,  (ppm)}: 0.17 (m, 1H, cyclopropyl (CH2)); 0.38-2.17 (24H); 0.76 (s, 6H, (CH3-18 and 20 CH3-19); 3.48 (m, 2H, CH2-OH); 3.84 (m, 1H, H-3); 4.13 (s , 1H, OH); 4.39 (m, 2H, 2 x OH); 4.83 (d, J = 3.8 Hz, 1H, OH-3).

 13C NMR {200 MHz, DMSO-d6,  (ppm)}: 7.9 (CH2); 14.5 (CH); 15.8 (CH); 18.9 (CH3); 19.4 (CH3); 22.0 (CH2); 22.2 (CH); 22.8 (CH); 27.0 (CH2); 27.3 (CH2); 27.7 (CH2); 33.5 (CH2); 34.2 (CH); 36.5 (CH2); 40.0 (C); 42.4 (C); 43.9 (CH2); 52.8 (CH); 62.1 (CH2); 63.9 (CH2); 66.8 (CH); 67.9 (CH); 72.9 (C); 80.8 (C). 25

 HPLC-MS (ESI): [(M-H2O) + H] + = 373

EXAMPLE 25

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 17- (3-hydroxypropyl) -6, 7, 15, 16-dimethylenandrostan-3, 5.17-triol (3.00 g, 0.008 mol) was dissolved in toluene (140 ml) at reflux and manganese dioxide (IV) (90%, 15.00 g, 0.155 mol) was added portionwise. After 6 hours at 82-85 ° C, more amount of oxidant (90%, 3.00 g, 0.031 mol) was added. When the reaction was completed, as indicated by TLC analysis, the mixture was cooled to room temperature and water (185 ml) and ethyl acetate (120 ml) were added. Manganese dioxide was quenched by adding oxalic acid (40.00 g) in portions while maintaining the temperature below 10 ° C. The mixture was vigorously stirred and the development of carbon dioxide was observed. After allowing the system to reach 20 ° C, the mixture was filtered by washing with ethyl acetate. The collected phases were separated, the aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic phases were washed with water (75 ml), saturated sodium bicarbonate (100 ml) and brine (75 ml, 55 ml).

 After removing the organic solvent at 50 ° C under reduced pressure, the crude product was obtained in the form of a yellow foam (2.05 g).

 Recrystallization from acetone gave the title compound (1.14 g, 0.003 mol, 37%)

 The analytical data are in accordance with those indicated in EXAMPLE 16.

EXAMPLE 26 (comparative)

17- (2- [1,3] Dioxan-2-ylethyl) -6, 7, 15, 16-dimethylenandrost-4-en-17-ol-3-one 15

 17- (2- [1,3] dioxan-2-ylethyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5.17-triol (14) was dissolved , 25 g, 0.032 mol) in toluene (550 ml) at reflux and manganese dioxide (IV) (90%, 57.00 g, 0.611 mol) was added portionwise. After stirring for 5 hours at 82-85 ° C, an additional amount of oxidant (90%, 5.00 g, 0.052 mol) was added. When the reaction was completed as indicated by TLC analysis, the mixture was cooled to room temperature and 20 water (900 ml) and ethyl acetate (350 ml) were added. Manganese dioxide was quenched by adding oxalic acid (116.00 g) in portions while maintaining the temperature below 10 ° C. The mixture was vigorously stirred and the development of carbon dioxide was observed. The solid was filtered by vigorously washing with ethyl acetate. The two collected phases were separated and the aqueous phase was extracted with ethyl acetate (300 ml). The combined organic phases were washed with water (500 ml), saturated sodium bicarbonate (400 ml) and water (2 x 300 ml). 25

 After removing the organic solvent at 50 ° C under reduced pressure, the product was obtained as an orange oil (15.73 g).

 The title compound was isolated by chromatography eluting with n-hexane: ethyl acetate (10.23 g, 0.024 mol, 75%).

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.38 (s, 1H, cyclopropyl (CH2)); 0.82-2.68 (25H); 0.93 (s, 3H, CH3-18); 1.10 30 (s, 3H, CH3-19); 3.7-3.85 (m, 2H, CH2-O); 4.10-4.18 (m, 2H, CH2-O); 4.62 (t, J = 4.4 Hz, 1H, O-CH-O); 6.01 (s, 1H, H-4).

 13C NMR {200 MHz, CDCl3,  (ppm)}: 7.8 (CH2); 15.9 (CH); 17.5 (CH); 18.9 (CH3); 19.0 (CH2); 19.1 (CH3); 20.1 (CH2); 21.1 (CH2); 22.9 (CH); 25.7 (CH); 29.7 (CH2); 31.0 (CH2); 33.9 (CH2); 34.7 (CH); 36.4 (CH2); 37.0 (CH2); 37.4 (C); 42.5 (C); 51.9 (CH); 52.4 (CH); 66.9 (2xCH2); 81.7 (C); 102.6 (CH); 125.6 (CH); 172.0 (C); 198.0 (C).

 HPLC-MS (ESI): [M + H] + = 427; [2 M + Na] + = 875 35

EXAMPLE 27 (comparative)

17- (2- [1,3] Dioxolan-2-ileyl) -6, 7, 15, 16-dimethylenandrost-4-en-17-ol-3-one

 The preparation of the title compound was analogous to that of EXAMPLE 26, starting from 17- (2- [1,3] dioxolan-2-yl-ethyl) -6, 7, 15, 16-dimethylen- 5-androstan-3, 5.17-triol (30.00 g, 0.069 mol).

 The crude product was a mixture of 17- (2- [1,3] dioxolan-2-yl-ethyl) -6, 7, 15, 16-dimethylene-androst-4-en-17 -ol-3 and drospirenone (HPLC analysis showed a 65:25 to 266 nm ratio). 5

 Column chromatography on silica gel performed on 15.3 g of the crude product, provided 0.66 g of drospirenone (0.002 mol), 5.05 g of 17- (2- [1.3] dioxolan-2 -ilethyl) -6, 7; 15, 16-dimethylenandrost-4-en-17-ol-3-one and 6.04 g of the mixture of the two products.

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.8-2.62 (14H); 0.94 (s, 3H, CH3-18); 1.10 (s, 3H, CH3-19); 3.90 (m, 2H, O-CH2); 4.02 (m, 2H, O-CH2); 4.96 (t, J = 4.5 Hz, 1 H, O-CH-O); 6.02 (s, 1H, H-4). 10

 13C NMR {200 MHz, CDCl3,  (ppm)}: 7.7 (CH2); 15.0 (CH); 16.0 (CH3); 17.5 (CH3); 18.8 (CH); 18.9 (CH2); 20.1 (CH); 21.1 (CH2); 22.8 (CH); 28.2 (CH2); 30.7 (CH2); 33.9 (CH2); 34.7 (CH); 36.0 (CH2); 36.3 (C); 37.4 (CH2); 42.5 (C); 51.9 (CH); 54.4 (CH); 68.8 (2xCH2); 81.7 (C); 104.8 (CH); 125.5 (CH); 172.1 (C); 184.3 (C).

 HPLC-MS (ESI): [M + H] + = 413; [2 M + Na] + = 847

EXAMPLE 28 (comparative) 15

17- (3,3-Dimethoxypropyl) -6, 7, 15, 16-dimethylene-androst-4-en-17-ol- 3-one

 The preparation of the title compound was analogous to that indicated in EXAMPLE 26, starting from 17- (3,3-dimethoxypropyl) -6, 7, 15, 16-dimethylen-5-androstan-3 , 5.17-triol (8.39 g, 0.019 mol). 5.50 g of the crude product were obtained. twenty

 A sample of the product was isolated by column chromatography, eluting with dichloromethane / methanol.

 1H NMR {200 MHz, CDCl3,  (ppm)}: 0.32 (m, 1H, cyclopropyl (CH2)); 0.65 (s, 3H, CH3-18); 0.80-2.14 (20H); 0.82 (s, 3H, CH3-19); 2.22-2.55 (m, 3H, CH2-C = O, OH); 3.34 (s, 6H, 2 x (OCH3)); 4.40 (t, J = 5.6 Hz, 1H, O-CH-O); 6.00 (s, 1 H, H-4).

 13C NMR {200 MHz, CDCl3,  (ppm)}: 7.7 (CH2); 15.2 (CH); 16.0 (CH3); 17.5 (CH3); 18.9 (CH); 19.0 (CH2); 20.1 25 (CH); 21.1 (CH2); 22.9 (CH); 27.1 (CH2); 31.5 (CH2); 33.9 (CH2); 34.7 (CH); 36.3 (C); 37.0 (CH2); 37.3 (CH2); 42.4 (C); 51.9 (CH); 52.5 (CH); 53.0 (2 CH3); 81.3 (C); 105.3 (CH); 125.6 (CH); 171.9 (C); 198.0 (C).

 HPLC-MS (ESI): [M + H] + = 415; [M + Na] + = 437 [2 M + Na] + = 851

EXAMPLE 29 (comparative)

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone) 30

 17- (3,3-dimethoxypropyl) -6, 7, 15, 16-dimethylenandrost-4-en-17-ol-3-one (0.434 g, 0.001 mol) was dissolved in 1.2 -dimethoxyethane (10 ml) at room temperature. Jones reagent (1.27 containing: 0.24 g of chromium oxide (VI), 0.65 g of water, 0.38 g of sulfuric acid) was added dropwise and the reaction was monitored by TLC. After 4 hours, ethyl acetate (20 ml) was added followed by a saturated solution of sodium pyrosulfite (15 ml). The mixture was stirred for 15 minutes and the two phases separated; The organic was washed with water (2 x 10 ml) and concentrated at 50 ° C under reduced pressure.

 The desired product was purified by column chromatography on silica gel (0.28 g, 0.0008 mol, 76%).

 The analytical data correspond to those indicated in EXAMPLE 16.

EXAMPLE 30 (comparative) 10

6, 7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21.17-carbolactone (Drospirenone)

 17- (2- [1,3] dioxolan-2-yl-ethyl) -6, 7, 15, 16-dimethylene-5-androstan-3, 5,17-triol was dissolved (1.50 g, 0.003 mol) in acetone (36 ml) at 25 ° C. A solution of potassium permanganate (1.10 g, 0.007 mol) in a water / acetone mixture (6.6 ml / 13.8 g) was added dropwise followed by sulfuric acid (96%, 0.20 ml , 0.004 mol); the temperature was raised to 35 ° C and the mixture was kept in a water bath.

 A few more portions of potassium permanganate (3.33 g, 0.021 mol) were added together with sulfuric acid (1.12 ml, 0.021 mol). At the end of the reaction (checked by TLC analysis), ethyl acetate (100 ml) was added followed by water / ice (70 g / 70 g), oxalic acid (3.12 g, 0.035 mol) and sodium pyrosulfite (3 , 80 g, 0.020 mol); The resulting mixture was stirred at 0-5 ° C for 15 minutes. After removing the colorless solid by filtration, the phases 20 were separated and the aqueous phase was extracted with ethyl acetate (70 ml). The combined organic phases were washed with brine (50 ml), saturated sodium bicarbonate (70 ml, 50 ml), water (50 ml) and concentrated at 45 ° C under reduced pressure to give a colorless semisolid (0.6 g).

 The product was isolated by column chromatography on silica gel, eluting with n-hexane: ethyl acetate) (0.4 g, 0.001 mol, 33%). 25

 The analytical data correspond to those indicated in EXAMPLE 16.

EXAMPLE 31

6,7, 15, 16-Dimethylene-3-oxo-17-pregn-4-en-21,17-carbolactone (Drospirenone)

 The preparation of the title compound was analogous to that indicated in EXAMPLE 27 starting from 6.30 g (0.009 mol) of 17- [3- (tert-butyldimethylsilyloxy) propyl] -6, 7, 15, 16 Dime-dimethylene-5-androstan-3, 5.17-triol crude which was reacted with potassium permanganate (7.43 g, 0.047 mol) and 3M sulfuric acid (7.8 ml, 0.023 mol) .

 After purification by column chromatography, the title compound (0.44 g, 0.0012 mol, 13%) was obtained. 5

 The analytical data correspond to those indicated in EXAMPLE 16.

Claims (8)

1. A process for the preparation of 6, 7, 15, 16-dimethylene-3-oxo-17-pregn-4-en-21,17-carbolactone (I) comprising the following steps:  1) react compound 6  5  with a compound of formula II: in which X is halogen and R- is -CH2-ORI, in which RI is one of the following hydroxyl protecting groups: i) a silyl derivative Q3Si-, wherein Q, independently of each other, represents (C1-C6) alkyl, aryl (C6-C10), alkylaryl (C1-C4) or alkoxyaryl (C1-C4), 10 ii) in which n is 1 or 2; whereby a compound 8 is obtained:  fifteen 2) oxidation of compound 8 with an oxidant based on MnIV / VII with removal of the RI protecting group, thereby providing drospirenone I: 2. A process according to claim 1, wherein step (1) is performed in an aprotic solvent in the presence of lithium. 3. A process according to claim 1, further comprising transforming compound II into the corresponding alkyl magnesium derivative prior to its reaction with compound 6. 5 4. A process according to claim 1, wherein said MnIV / VII based oxidant is selected from MnO2 and KMnO4. 5. A process according to claim 1, wherein in step 2) the compound 8, wherein R = CH2-ORI wherein RI is Q3Si and Q is as defined in claim 1, it is oxidized first with manganese dioxide, to produce intermediate 9, which is then hydrolyzed to remove the RI group, thereby producing intermediate 10: which is finally oxidized to give lactone with manganese dioxide, thus producing drospirenone. 6. A process according to claim 1, wherein in step 2) compound 8, wherein R = -CH2-ORI wherein RI is Q3Si and Q is as defined in claim 1, is hydrolyzes to give intermediate 11: 15 which is then oxidized with manganese dioxide to produce drospirenone. 7. A process according to claim 1, further comprising the following steps for the preparation of 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androstan-17-one (compound 6): a) epoxidation of 7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androsten-17-one (1) with tert-20 butyl hydroperoxide in the presence of vanadyl acetylacetonate in toluene at 70- 75 ° C, to give 5,6-epoxy-7-hydroxy-15, 16-methylene-3-pivaloyloxy-5-androstan-17-one 2: b) reacting compound 2 with hexachloroacetone in dichloromethane added together with triphenylphosphine at a temperature of 0-5 ° C followed by heating at 10-15 ° C, to give 7-chloro-5,6-epoxy-15, 16- methylene-3-pivaloyloxy-5-androstan-17-one 3:  5 c) opening the epoxy ring of compound 3, with simultaneous removal of the chlorine atom, by reaction with acetic acid, zinc and copper bromide in 1,2-dimethoxyethane by heating to 70 ° C, to obtain 5-hydroxy-15, 16 -methylene-3-pivaloyloxy-5-androst-6-en-17-one 4: d) removal of the pivaloyl group in position 3 of compound 4 with potassium hydroxide in a tetrahydrofuran / methanol mixture in the presence of sodium perchlorate at room temperature, followed by the addition of sulfuric acid at pH 7, whereby 3 is obtained , 5-dihydroxy-15, 16-methylene-5-androst-6-en-17-one 5: e) conversion of compound 5 into 3, 5-dihydroxy-6, 7, 15, 16-dimethylene-5-androst-17-one 6 by reaction with dibromomethane in 1,2-dimethoxyethane in the presence of zinc and copper bromide by heating to 75 ° C, followed by the addition of acetic acid and isopropanol: 8. A compound that is selected from the group consisting of: wherein R is as defined in claim 1.